Adult-onset Still's disease: analysis of a monocentric cohort of patients.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a multigenic autoinflammatory disease with a severe systemic involvement. Because of the rarity of the disease, most published cohorts are multicentric. The aim of this report is to describe a monocentric cohort of AOSD patients, reporting clinical features and response to therapy in a long follow-up. METHOD: Thirty-eight patients, attending the Clinical Immunology Unit and fulfilling Yamaguchi, Fautrel, or Daghor-Abbaci classification criteria for AOSD, were recruited for this study. In all patients, clinical and serological data were collected at diagnosis and every 6 months thereafter. The Pouchot score was calculated at every visit. RESULTS: Fever, arthromyalgia, and skin rash were the most frequent manifestations, followed by lymphadenopathy, sore throat, arthritis, splenomegaly, hepatic involvement, pleuropericarditis, and weight loss. As far as the disease course is concerned, 25% presented a monocyclic and 35% a polycyclic pattern, and 40% developed chronic articular involvement. Severe complications were observed at disease onset in 21% of the patients. All of the patients were treated with steroids; 74% also received conventional synthetic disease-modifying anti-rheumatic drugs (methotrexate in most cases) and 71% biological disease-modifying anti-rheumatic drugs (interleukin-1 inhibitors in most cases). Therapeutic switching for lack/loss of efficacy or adverse drug reactions was necessary in 66%. CONCLUSION: The analysis of this cohort confirms that AOSD is a complex, severe, and heterogeneous disease. However, despite long-term treatment and comorbidities, therapies are effective and well tolerated. The therapeutic armamentarium now available allows long-lasting remission with low immunosuppression to be achieved in most patients.

The role of heavy metals and polychlorinated biphenyls (PCBs) in the oncogenesis of head and neck tumors and thyroid diseases: a pilot study.

Previous literature has highlighted the mechanisms of molecular toxicity induced by substances such as arsenic, cadmium, chromium, nickel, lead, barium and PCBs. The research was carried out on 20 volunteers, all the patients gave their consent to the research: the aim of the study was to evaluate the presence of metals and PCBs in these different matrices (blood and hair), correlating the biochemical data to pathological conditions present, and also to the area in which patients resided. Various quantitative determinations were carried out on samples of blood and hair for 14 heavy metals and on blood samples for 12 PCBs. For the 11 patients the results indicated that blood levels for half of the 14 displayed heavy metals measured considerably higher compared to the reference values, whilst the levels measured in hair evidenced some positive values significantly higher than the maximum reference. Of the 12 PCBs assayed in blood some showed higher positive values compared to the maximum tabular reference (although there is no clear reference quantified in the WHO-2005 report). In the 9 healthy patients heavy metals in the blood were within the expected target range, with those showing positive results (≤ 3 out of 14 heavy metals for each patient) having values only slightly higher than the reference maximum. The levels of 14 heavy metals measured in hair were below thresholds, and levels for the 12 PCBs measured in blood showed negativity or positivity with values close to the minimum benchmarks. The analyses carried out on biological matrices have uncovered important and significant differences between healthy and unhealthy subjects, both qualitative and quantitative differences with respect to heavy metals and PCBs. All patients with head and neck cancer enlisted for the study had heavy metal and PCB blood levels at least twice the maximum reference level. The levels of heavy metals in hair were at least double the maximum reference. In contrast, all healthy volunteers enrolled showed no significant levels for either metals or PCBs.

Integrating behavioral assessment in instructional design for competency-based medical education.

As institutions continuously strive to align with the standards set forth within competency-based medical education, there is an increased need to produce evidence of learner achievement in the form of observable behaviors. However, the complexity of healthcare education and clinical environments make it challenging to generate valid and reliable behavioral assessments. In this article, we utilize our interdisciplinary knowledge from the perspectives of experts in medical education, assessment, and academic administration to provide tips to successfully incorporate behavioral assessments into instructional designs. These include tips for identifying the best assessment methods fit for purpose, guiding instructors in establishing boundaries of assessment, managing instructors, selecting raters, generating behavioral assessment guides, training raters, ensuring logistics support assessment strategies, and fostering capacity for iteration. These can be used by institutions to improve planning and implementation for longitudinal behavioral assessments.

Treatment of horizontal canal benign paroxysmal positional vertigo: a new rehabilitation technique.

The aim of this study was to evaluate the effectiveness of a new technical variant applied to the Gufoni's manoeuvre, in the treatment of horizontal canal benign paroxysmal positional vertigo (HSC-BPPV). 87 patients with BPPV of HSC (55 women and 32 men), aged between 21 and 80 years, were randomized either to modified Gufoni's manoeuvre or to the Gufoni's manoeuvre. 93% of patients treated with modified Gufoni's manoeuvre was cured after the first treatment session, of which only 2% had a conversion into PSC-BPPV, while the Gufoni's manoeuvre led to a symptoms resolution in 88% of cases, of which 16% had a conversion into PSC-BPPV. Therefore, the modified Gufoni's manoeuvre shows the same effectiveness in the resolution of symptoms of Gufoni's manoeuvre, but it appears more effective than the latter to reduce the percentage of conversion of the HSC-BPPV into PSC-BPPV (χ(2) = 6.13, P = 0.047).

Manufacturing, installation, commissioning, and first results with the 3D low-temperature co-fired ceramic high-frequency magnetic sensors on the Tokamak à Configuration Variable.

Innovative high-frequency magnetic sensors have been designed and manufactured in-house for installation on the Tokamak à Configuration Variable (TCV), which are now routinely operational during the TCV experimental campaigns. These sensors combine the Low Temperature Co-fired Ceramic (LTCC) and the classical thick-film technologies and are in various aspects similar to the majority of the in-vessel inductive magnetic sensors foreseen for ITER (around 450 out of the 505 currently being procured are of the LTCC-1D type). The TCV LTCC-3D magnetic sensors provide measurements in the frequency range up to 1 MHz of the perturbations to the wall-aligned toroidal (δBTOR), vertical (δBVER), and radial (δBRAD) magnetic field components. Knowledge of the equilibrium at the last closed flux-surface allows us to then obtain the field-aligned parallel (δBPAR ∼ δBTOR), poloidal (δBPOL), and normal (δBNOR) components, the latter being in most cases rather different from the vertical and radial components, respectively. The main design principles were aimed at increasing the effective area and reducing the self-inductance of the sensor in each of the three measurement axes, which are centered at the same position on each sensor, while reducing the mutual and parasitic coupling between them by optimizing the on-board wiring. The physics requirements are set by the installation of two high-power/high-energy neutral beam injection systems on TCV, i.e., studying fast ions physics, coherent instabilities, and turbulence in the (super-)Alfvénic frequency range. In this paper, we report the manufacturing, installation, and commissioning work for these high-frequency LTCC-3D magnetic sensors and conclude with an overview of illustrative experimental results obtained with this system. The LTCC-3D data provide new insights into the δBPOL coherent (eigenmodes, up to ∼400 kHz) and in-coherent background turbulent fluctuations in the higher frequency range up to ∼1 MHz, which were not previously available with the TCV Mirnov sensors. Furthermore, the LTCC-3D δBPOL measurements allow us to cross-check the data obtained with the standard Mirnov coils and have led to the identification of largeelectromagnetic (EM) noise pick-up for the Mirnov data acquisition (DAQ). When the sources of EM noise pick-up on the Mirnov DAQ are removed, the LTCC-3D data for δBPOL are in good overall agreement, i.e., within the expected measurement uncertainties, with those obtained with the standard Mirnov sensors located at the same poloidal position in the frequency range where the respective data acquisition overlap, routinely up to 125 kHz and up to 250 kHz in some discharges. The LTCC-3D δBPAR measurements (not previously available in TCV or elsewhere) provide evidence that certain instabilities have a finite parallel δB at the wall, hence at the LCFS, consistent with the recent theoretical results for pressure-driven modes. The LTCC-3D δBNOR measurements improve significantly on the corresponding measurements with the saddle loops, which are mounted onto the wall and have a bandwidth of ∼3 kHz (due to the wall penetration time). A detailed end-to-end system modeling tool has been developed and applied to test on the simulated data the actual measurement capabilities of this new diagnostic system and obtain the ensuing estimates of the intrinsic measurement uncertainties. A detailed error analysis is then performed so that, finally, fully calibrated, absolute measurements of the frequency-dependent amplitude and spectral breaks of coherent eigenmodes and in-coherent broadband magnetic fluctuations are provided for the first time in physical units with quantitative uncertainties.

Nasotracheal prolonged safe extubation in acute respiratory failure post-thyroidectomy: An efficacious technique to avoid tracheotomy? A retrospective analysis of a large case series.

BACKGROUND: Acute respiratory failure is a rare life threatening complication following thyroid surgery and its incidence is reported as high as 0.9%. Clinical presentation of severe acute respiratory failure is characterized by dyspnea, inspiratory airways distress, hypoxia and its standard current management is the orotracheal intubation and safe extubation. In case of persistent distress, tracheotomy is mandatory. The Authors, analysing a large acute respiratory failure clinical series, describe an innovative treatment of this severe condition: the nasotracheal prolonged safe extubation. METHODS: Patients treated at our Intensive Care Unit for acute respiratory failure following thyroid surgery from January 2004 to December 2013, were reviewed. Demographic data including gender, age, clinical presentation, laryngoscopic findings, management and outcome during a 24-months follow-up after treatment were collected and evaluated. Moreover, the strategy for prolonged nasotracheal safe extubation was carefully described. RESULTS: Nineteen out of the 2853 patients scheduled for thyroid surgery (0.66%) at our University Hospital, developed post-operative acute respiratory failure. All of them were treated by nasotracheal prolonged safe extubation. The success rate in avoiding highly invasive treatment was of 84.2%, since only 3 patients needed definitive tracheotomy (15.7%). CONCLUSIONS: In our series, the prolonged safe extubation reduced the almost totality of expected tracheotomies in patients with acute respiratory failure following thyroid surgery (84.2%), demonstrating its feasibility and efficacy. It was a well tolerated and minimal invasive procedure that allowed a good respiratory ability and a fast clinical resolution of the laryngeal functional impairment.

Unintentional recurrent laryngeal nerve injuries following thyroidectomy: Is it the surgeon who pays the bill?

BACKGROUND: Thyroidectomy is one of the most common intervention in general surgery and, after the turn of the century, its rate has sharply increased, along with a worldwide increased incidence of differentiated thyroid cancers. Therefore, injuries of the recurrent laryngeal nerve have become one of the most frequent cause of surgical malpractice claims, mostly following surgery for benign pathology. MAIN BODY: Even if the incidence of definitive paralysis is generally lower than 3%, during the last 20 years in Italy, the number of claims for damages has sharply raised. As a consequence, a lot of defensive medicine has been caused by this issue, and a witch-hunt has been accordingly triggered, so determining mostly a painful and lasting frustration for the surgeons, who sometimes are compelled to pay a lot of money for increasing insurance premiums and lawyers fees. Recurrent laryngeal nerve injury should be considered as a potentially catastrophic predictable but not preventable event, rather than the result of a surgical mistake. CONCLUSION: Purposes of the Authors are analyzing incidence, conditions of risk, and mechanisms of recurrent laryngeal nerve injuries, underlining notes of surgical technique and defining medical practice recommendations useful to reduce the risk of malpractice lawsuits and judgments against surgeons.

Outcome assessment in patients with chronic obstructive rhinitis CO2 laser treated.

Surgical lasers have been used to restore nasal flow in chronic obstructive rhinitis, with a significant improvement in symptoms having been reported in almost all cases. However, evidence supporting the efficacy at long-term, and studies on the assessment of quality of life remain limited. In the present study, efficacy at long term and improvement in the quality of life were assessed in patients with chronic obstructive rhinitis, treated with CO2 laser. A total of 308 patients with chronic obstructive rhinitis were enrolled. The primary outcome measure assessed was the change in score regarding specific and general symptoms, between baseline to 2-4.5 and 7.8 mean years follow-up. Laser turbinotomy restored nasal flow and induced a change in total score which was statistically significant, for specific and general symptoms at the first, second and third follow-up, p < 0.01. CO2 laser turbinate surgery improved symptoms and quality of life in patients with chronic obstructive rhinitis as observed at 2-4.5 and 7.8 mean years follow-up.

Submandibular gland myoepithelioma.

Benign myoepithelioma is a very rare form of salivary gland tumor, composed entirely of myoepithelial cells. It accounts for approximately 1% of all salivary gland tumors and is most frequently located in the parotid gland and in the minor salivary glands of the hard palate. We describe herein the ninth reported case of myoepithelioma of the submandibular gland. Benign myoepithelioma must be differentiated from several benign and malignant epithelial and mesenchymal tumors. Immunohistochemical staining can help differentiate between these conditions, but histopathology remains the gold standard for diagnosing this neoplastic process.

Mucoepidermoid carcinoma of the base of tongue.

Mucoepidermoid carcinoma (MEC) is the most common malignant, locally-invasive tumour of the salivary glands, and accounts for approximately 35% of all malignancies of the major and minor salivary gland. Minor salivary glands are scattered in different areas of the oral cavity such as palate, retromolar area, floor of the mouth, buccal mucosa, lips and tongue. MECs of tongue base are not common. We present a rare case of MEC localised at the tongue base in a 42-year-old Caucasian woman and discuss the histopathological types, management and review the literature. Adequate intra-oral excision was the treatment of choice in this case and in low-grade MEC. Prognosis of MEC is a function of the histological grade, adequacy of excision and clinical staging.

Modification of mRNA secondary structure and alteration of the expression of human interferon alpha 1 in Escherichia coli.

A plasmid (pNL015) was constructed to contain a human interferon alpha 1 (IFN-alpha 1) gene under the transcriptional control of the Escherichia coli lipoprotein promoter. The E. coli cells harboring this plasmid produce 2.8 x 10(4) units/ml of IFN. Secondary structure analysis of the transcripts produced by pNL015 showed that the coding region could base pair with the Shine-Dalgarno (SD) region with a delta G = -3.9kcal/mol. A new plasmid pNL008 was constructed by modifying pNL015 with an 11-bp deletion and a 2-bp insertion in the coding region, so that the SD region is not involved in the secondary structure. E. coli cells harboring pNL008 produce ten times more IFN activity than cells harboring pNL015. A series of experiments were carried out to show that the specific activities of IFN, differential rates of IFN transcription, protein degradation or mRNA degradation could not account for the difference observed in expression. A rigorous test on this model of translational inhibition was conducted by the construction of pNL017 with a single bp substitution which did not change the amino acid sequence of the IFN (synonymous codon substitution) but which increased the calculated energy of interaction with the SD sequence to delta G = -10.8 kcal/mol. The E. coli cells harboring pNL017 produced no detectable IFN activity.

Cloning of eukaryotic genes in single-strand phage vectors: the human interferon genes.

Using oligonucleotide probes with defined sequences, we have selected clones from a human lymphocyte cDNA library which represent human leukocyte (HuIFN-alpha) and fibroblast (HuIFN-beta) interferon gene sequences. Double-stranded f1 phage DNA was used as the vector for initial cloning of cDNA. Clones carrying interferon gene sequences were identified by hybridization with the oligonucleotide probes. The same oligonucleotide probes were used as primers for dideoxy chain termination sequencing of the clones. One HuIFN-alpha clone, 201, has a nucleotide sequence different from published HuIFN-alpha sequences. Under control of the lacUV5 promoter, the 201 gene has been used to express biologically active HuIFN-alpha in Escherichia coli.

Interferon-alpha 8b is the only variant of interferon-alpha 8 identified in a large human population.

Three variants of human interferon (IFN)-alpha 8a gene, that is, IFN-alpha 8b, and IFN-alpha 8c, have been reported previously. They differ from each other by changes in their coding region at nucleotide positions 359-360, 372, and 550. Human genomic DNA obtained from over 28,000 healthy blood donors and from 4 human cell lines was used in the polymerase chain reaction (PCR) designed for specific amplification of the IFN-alpha 8 gene fragments. The resulting PCR product was analyzed by (1) restriction endonuclease digestion, (2) DNA sequencing, and (3) allele-specific secondary PCR amplification. Only one sequence for IFN-alpha 8 was identified, and that was for IFN-alpha 8b. The sequences for IFN-alpha 8a and IFN-alpha 8c were not detected after PCR amplification either in the pooled leukocytes obtained from > 28,000 individuals or in cell lines tested. These data suggest that the naturally occurring variant or allele for IFN-alpha 8 in the population is IFN-alpha 8b. IFN-alpha 8a and IFN-alpha 8c variants were consistently below the level of detection of the assays and, if present at all in the population, are very rare.

Cognitive dysfunction and impaired organization of complex motility in degenerative parkinsonian syndromes.

BACKGROUND: A frontostriatal pattern of cognitive decline, consisting of a frontal lobe-like syndrome without genuine cortical defects such as amnesia, apraxia, aphasia, or agnosia, is well established in basal ganglial diseases. Recent pathological investigations, however, have again noted cortical damage in progressive supranuclear palsy (PSP), suggesting that cortical defects could be present. OBJECTIVES: To delineate the pattern of cognitive impairment and to detect higher-order motor impairments (including ideomotor apraxia) in parkinsonian syndromes. PATIENTS AND METHODS: We assessed ideomotor apraxia, and simple and sequential tapping in patients with Parkinson disease, multiple system atrophy, and PSP with similar disease severity, age range, and education. We also administered a comprehensive battery of neuropsychological tests to examine general intelligence, memory, executive functions, attention, and visuospatial orientation. The results were compared between groups and with a matched normal control group. RESULTS: Sequential tapping and the imitation of sequences of gestures were impaired in all patient groups, with patients with PSP performing worse than the other groups. Based on ideomotor apraxia scores and a qualitative analysis of errors, 3 patients with PSP and 2 with multiple system atrophy were considered apraxic. General intelligence and executive functions were compromised in all patient groups. The impairment of patients with PSP was more pervasive than that of the other groups, and included compromise of visuospatial functions, attention, and memory. Discriminant analysis of all cognitive and motor tests showed that the tapping and ideomotor apraxia tests best identified the patients vs control subjects. CONCLUSIONS: The presence of cortical as well as subcortical damage in patients with PSP and those with multiple system atrophy is indicated by the presence of pervasive cognitive and motor disturbances in the former, substantial motor disorganization in the latter, and the finding of ideomotor apraxia in some patients with these diseases. Furthermore, the discovery that tests of motor and gesture best identified all patients vs control subjects is consistent with the existence of a common motor disorganization in these parkinsonian syndromes, in agreement with the known damage to the corticostriatal pathways in these conditions.

Different relative activities of human cell-derived interferon-alpha subtypes: IFN-alpha 8 has very high antiviral potency.

Interferon-alpha (IFN-alpha) subtypes were separated by HPLC from the IFN mixtures produced by virus-stimulated human lymphoblastoid cells and leukocytes. Together with preparations of lymphoblastoid IFN and recombinant IFN-beta, these were tested in three human tumor cell lines derived from liver, lung, and neuroblasts. Their relative antiviral activities differed markedly: subtype IFN-alpha 8 was the most potent and IFN-alpha 1 the least. The results were broadly similar in all three cells, with some minor differences. when the same preparations were tested for inhibition of thymidine incorporation, the relative activities were quite different: subtypes IFN-alpha 10, IFN-alpha 17, IFN-alpha 21, and IFN-alpha 5 were now the most active, and IFN-alpha 2 was the least active. IFN-alpha 1 and IFN-alpha 8 had comparable intermediate activity. Thus, the differences in activity were not caused by degradation of some subtypes during their separation. IFN-alpha 8 not only had the greatest antiviral activity but also, like IFN-beta, induced an antiviral state in U1 mutant cell lines, which lack the tyrosine kinase, Tyk2, required for signal transduction by other IFN-alpha subtypes.

Interferon-alpha 2 variants in the human genome.

Variants of human leukocyte interferon alpha 2 (IFN-alpha 2a, alpha 2b, and alpha 2c) differ from each other by changes in their coding regions at nucleotide positions 137 and 170. As a result of these nucleotide variations, the DNA sequences of the three variants can be distinguished by selective restriction enzyme analysis. Human genomic DNA obtained from over 28,000 normal healthy individuals was used as templates in the polymerase chain reaction (PCR) to amplify the human IFN-alpha 2 gene sequence. The resulting PCR products were analyzed with restriction nucleases to identify the specific IFN-alpha 2 variant sequences present in the genomic DNA of the population examined. The results show that IFN-alpha 2b was detected as the predominant species and IFN-alpha 2c as a very minor species (< 0.1%). The IFN-alpha 2a gene was not detected in this population.

Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18 positron emission tomographic study.

OBJECTIVE: To evaluate the regional cerebral metabolic involvement; the relationships among regional brain metabolism, clinical features, and quantitative measures of disease severity; and the patterns of brain involvement that can be related to the different types of onset: striatonigral degeneration vs olivopontocerebellar atrophy. DESIGN: Fludeoxyglucose F 18 positron emission tomography (PET) studies performed in patients with multiple system atrophy (MSA) were evaluated for their clinical features at the onset of the disease and at the time of the PET study. CASES: Seventeen patients diagnosed as having probable MSA and 10 age-matched controls. RESULTS: The hypometabolism in the putamen-pallidum complex and in the cerebellum was the best discriminant for disease classification. The efficacy of levodopa treatment was positively correlated with the metabolic activity of the putamen-pallidum complex. The patients with olivopontocerebellar atrophy type (N = 8) had a prevalent hypometabolism in the cerebellum, while the patients with striatonigral degeneration type (N = 9) had a prevalent impairment in the pallidum-putamen complex. We demonstrated a negative correlation between (1) severity of parkinsonism and metabolic values of putamen and caudate; (2) severity of cerebellar signs and metabolism in the cerebellum; and (3) autonomic dysfunction and metabolic activity in the thalamus, frontal, and temporal regions, bilaterally. CONCLUSIONS: These findings support the selective metabolic reduction in the putamen and cerebellum as a marker of MSA. The clinical/metabolic correlations, demonstrating the expected dependence of extrapyramidal and cerebellar signs by dysfunction of basal ganglia and cerebellum, also support a possible involvement of central nervous system structures in autonomic control.

Clinical and magnetic resonance features of the classic and akinetic-rigid variants of Huntington's disease.

We studied 32 patients with confirmed Huntington's disease (HD); six (mean age, 31.7 years) had the akinetic-rigid form and 26 (mean age, 46.1 years) had the classic hyperkinetic form. Clinical examination included a count of abnormal involuntary movements, motor self-sufficiency evaluation by the Physical Disability Rating Scale, cognitive function assessment by the Mini-Mental State examination, and a verbal fluency test. Magnetic resonance imaging permitted measurement of bicaudate diameter, a sensitive indicator of caudate atrophy in HD. Patients with the akinetic-rigid form of HD were younger and had earlier disease onset than those with the classic form of HD. All patients with akinetic-rigid HD (group 1) had striatal hyperintensity on T2-weighted magnetic resonance images; seven patients with classic HD (group 2) had a similar abnormality. Groups 1 and 2 were in fact similar in all other respects, except that the number of abnormal involuntary movements was greater in group 2. Groups 1 and 2 together had significantly younger age at onset, lower Mini-Mental State Examination score, more severe motor disability, worse verbal fluency test result, and greater bicaudate diameter than the 19 patients with classic HD without magnetic resonance signal abnormality (group 3) and appear to be a uniform population, distinct from group 3. The abnormalities on magnetic resonance images indicated greater striatal damage in groups 1 and 2, which could be the neuroanatomic substrate of their greater motor and cognitive compromise.